This invention relates to a novel synthetic approach to compounds of Formula I. 
Phenylbutyric acid and its pharmaceutically acceptable derivatives are particularly preferred targets of the present invention. Sodium phenylbutyrate has been used extensively for the treatment of urea cycle disorders (Batshaw et al., Brusilow et al. (Ped. Research), Brusilow et al. (New Eng. J. Med.), Finkelstein et al., Maestri et al., Redonnet-Vernhet et al., Rowe et al.). Phenylbutyrate derivatives have also shown promising pharmaceutical properties in the treatment of sickle cell anemia (Collins et al., Dover et al. (New Eng. J. Med.), Dover et al. (Blood)). cystic fibrosis (Bradbury et al., Loffing et al.), AIDS (Roberts et al.), and several types of cancer (Carducci et al., Darmanun et al., Englehard et al., Gorospe et al.).
In the past, phenylbutyrate derivatives have been prepared by the Arndt-Einstert reaction, using diazomethane with silver oxide and sodium thiosulfate (J. Chem. Soc., 1997-99 (1938)). Alternatively, thianapthene-2-acetic acid and thianapthene-3-acetic acid have been used to prepare xcex2-phenylbutyric acid (J. Am. Chem. Soc., 70, 3768 (1948)). The Gignard reagent, benzyl magnesium chloride, has also been used in the synthesis of phenylbutyric acid, resulting in a yield of 16.1% (J. Am. Chem. Soc., 71, 2807-2808 (1949)).
It would be advantageous to have a synthetic route to phenylbutyrate and derivatives thereof that is not hindered by the synthetic restrictions, i.e., the necessity to vigorously exclude moisture from diazomethane and Grignard reagents, and that would give higher yields of product than the reactions described above.
One aspect of the present invention is a method of preparing a compound of Formula I: 
wherein R is independently selected from hydrogen, halo, C1-C4 alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, C1-C4 alkoxy, alkenoxy, alkynoxy; and X is hydrogen, an alkali metal cation, an ammonium or a substituted ammonium. According to one embodiment of the invention, the method comprises the steps of,
a) reacting a compound of Formula II; 
wherein R is as defined above, with a compound of Formula III; and 
b) reacting the resulting compound with a compound of Formula IV;
Xbxe2x80x94Zcxe2x80x83xe2x80x83Formula IV
where X is as defined above, and Z is hydroxy, sulfate, phosphate, bicarbonate, carbonate, or alkoxy, and b and c are independently 1-5. A particularly suitable compound of Formula IV is sodium hydroxide.
According to one aspect of the invention the reaction of a compound of Formula I with the compound of Formula II is conducted in the presence of a catalyst. Particularly suitable catalysts are Lewis acids, including, but not limited to aluminum chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, or sulfuric acid.
A particular aspect of the present invention is a method of preparing a 4-phenylbutyric acid by reacting benzene with butyrolactone.
It will be recognized by one skilled in the art based on the following description and illustrative examples that the present invention is a method of synthesizing compounds of Formula I: 
wherein R is independently selected from hydrogen, halo, C1-C4 alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, C1-C4 alkoxy, alkenoxy, alkynoxy; and X is hydrogen, an alkali metal cation, an ammonium or a substituted ammonium.
It will of course be appreciated that in the development of any such actual embodiment, numerous implementation-specific decisions must be made to achieve the developers"" specific goals, such as compliance with system-related and business-related constraints, which will vary from one implementation to another. Moreover, it will be appreciated that such a development effort might be complex and time-consuming, but would nevertheless be a routine undertaking for those of ordinary skill in the art having the benefit of this disclosure.
The method of the present invention comprises the steps of a) reacting a compound of Formula II; 
with a compound of Formula III. 
A particularly preferred compound of Formula II is benzene. According to one embodiment of the present invention, the reaction is conducted in a solvent. According to an alternative embodiment, the compound of Formula II is itself the solvent for the reaction.
A catalyst may be used to facilitate the reaction of the compound of Formula II with the compound of Formula III. One preferred class of catalysts is Lewis acids. Examples of particularly preferred catalysts are aluminum chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, and sulfuric acid.
According to one embodiment of the invention, the catalyst is added to a mixture of a compound of Formula II and an appropriate solvent or to neat compound of Formula II, if no solvent is used. This mixture is maintained, preferably with stirring, at a temperature between about xe2x88x9280xc2x0 C. and the boiling point of the solvent at ambient pressure. Preferably the mixture is maintained between 0xc2x0 C. and the boiling point of the solvent. The mixture of a compound of Formula II and catalyst can be stirred for a time ranging from several seconds to several days before a compound of Formula III is added to the mixture. Preferably, the mixture of a compound of Formula II and catalyst is stirred for a time ranging from about 1 min to about 30 min before a compound of Formula III is added.
The compound of Formula III can be added to the mixture of a compound of Formula II and catalyst as a neat reagent, or can be added as a solution in an appropriate solvent. The compound of Formula III is added dropwise, in small aliquots, or as a large portion. Subsequent to the complete addition of a compound of Formula III, the reaction mixture is maintained, preferably with stirring, at a temperature between about xe2x88x9280xc2x0 C. and the boiling point of the solvent at ambient pressure. Preferably the mixture is maintained between 0xc2x0 C. and the boiling point of the solvent. The reaction mixture can be so maintained for a time ranging from a few seconds to about 24 hr. Preferably, the reaction mixture is maintained about 10 min to about 180 min, more preferably from about 60 min to about 120 min.
The reaction mixture can be quenched via the addition of a quenching agent. Suitable quenching agents are of Formula IV:
Xbxe2x80x94Zcxe2x80x83xe2x80x83Formula IV
where X is as defined above, and Z is hydroxy, sulfate, phosphate, bicarbonate, carbonate, or alkoxy, and b and c are independently 1-5. Quenching agent can be added neat or as a solution in an appropriate solvent. A particularly preferable quenching agent is an aqueous solution of base. A preferred base is sodium hydroxide. Another preferred quenching agent is a mixture of a solution of aqueous base and ice.
The quenched solution can be maintained at a temperature from about 0 to about 50xc2x0 C. for a time ranging from a few minutes to about 10 hr, preferably from about 1 hr to about 3 hr. The pH of the solution can be maintained from about 6.5 to about 10, preferably from about 9 to about 9.5. The pH of the solution can be further raised by the addition of base. The quenched solution can be purified by filtration to remove any particulate that can be present. The quenched solution can be further purified by contacting it with an organic solvent to extract remaining starting materials, side products, and impurities. Examples of suitable extraction solvents include chloroform, dichcloromethane, trichloromethane, carbontetrachloride, and diethyl ether. The product can be precipitated from the aqueous solution by the addition of acid. The product can be isolated by filtration, or extracted into a suitable organic solvent. If the product is extracted into an organic solvent, it can be recovered upon evaporation of the solvent.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.